EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To explore associations of current serum α-tocopherol, current and past vitamin E supplement use and past dietary intake with memory (amnestic) and mixed domain impairment in older women.

Inclusion Criteria:

Age 60 years or older
No history of Alzheimer's disease, dementia, stroke, traumatic brain injury, other neurologic disease (such as Parkinson's), mental illness requiring hospitalization or alcohol or substance abuse
No current use of neuroleptics or long-term use of other major psychoactive medications
Vision and hearing acuity sufficient for valid neuropsychological testing
Individuals taking antidepressants related to situational stress were not excluded.

Exclusion Criteria:

Exclusion criteria for the Women's Health Initiative (WHI) were described elsewhere.

Description of Study Protocol:

Recruitment

Data used for the study was from the baseline assessment of participants in the Cognitive Change in Women (CCW) study, a single-site ancillary study to the WHI
Participants were recruited from either the WHI Observational Cohort or the control ("usual diet") group of the WHI Diet Modification are the Northwestern University (NU)/Evanston Hospital clinical center
These women were not enrolled in any treatment trials
Women aged 50 to 79 were recruited to the NU WHI clinical centers form geographic areas surrounding the clinical centers by methods including direct mailings, radio and television public service announcements and flyers
Respondents were screened for eligibility for the WHI randomized clinical trials during a series of three clinical visits
Those ineligible for or unwilling to participate in the clinical trials were offered participation in an observational study of health and lifestyle (the WHI Observational Study).

Design

Cross-sectional study.

Statistical Analysis

Cross-classification and the x² test of association were used to examine the bivariate relationships between the categorical exposure measures and the presence of each domain-specific impairment and the presence of mixed-domain impairment
For those impairments in which any significant bivariate association was found, multiple logistic regression analysis was used to investigate multivariate associations of exposures and covariables on cognitive impairment
Lag time (number of days between WHI baseline and ancillary study measurements) was included in models with past vitamin E intake
Additional potential confounders or effect modifiers were added to the model to determine their effect but were not retained in the final model unless they made a significant (P<0.05) contribution
The pair wise correlations of the four measures of vitamin E intake and serum level were assessed by the Kendall tau, a non-parametric correlation coefficient suitable for dichotomous measures.

Data Collection Summary:

Timing of Measurements

Measurements made at baseline.

Dependent Variables

Memory and mixed-domain cognitive impairment as determined from a battery of neuropsychological tests selected to sample cognitive domains.

Independent Variables

Vitamin E intake
Serum α-tocopherol.

Control Variables

Age
Education
Race
Geriatric Depression Scale (GDS) score
American National Adult Reading Test (ANART) score
History of cardiovascular disease
History of tobacco smoking
APOE genotype.

Description of Actual Data Sample:

Initial N: 1,201 women were sent mailings
Attrition (final N): 544 were screened as eligible and enrolled.

Age

60 to 69 years	45%
70 to 79 years	46%
80 years or more	9%

Ethnicity

Black, non-Hispanic	9%
White, non-Hispanic	87%
Asian/Pacific Islander	2%
Hispanic/Latino	0.8%
American Indian/Alaskan Native	0.2%
More than one race	0.6%

Other Relevant Demographics

Current vitamin E supplement use	78%
Previous vitamin E supplement use (WHI baseline)	60%
Previous dietary vitamin E (WHI baseline)
Less than 8mg per day	48%
8mg or more per day	52%

Anthropometrics

APOE Genotype
1/3	Less than 1%
2/3	11%
3/3	65%
3/4	20%
4/4	2%

Location

Evanston, IL, US.

Summary of Results:

Key Findings

Memory Tests At Baseline

24% of participants exhibited at least one impaired score on memory tests at baseline. Also:
- 16% on tests of visual spatial perception
- 8% on tests of executive function
- 5% on tests of language
- 3% on tests of attention
When domain-specific impairments were considered together, 12% of participants exhibited mixed-domain impairment. Of the 61 women with impairment in two or more domains, 82% had memory impairment and 11 had impairment in two or more domains, not including memory.

Bivariate Analysis

When bivariate associations between vitamin E measures and memory and mixed domain impairments were considered, neither energy-adjusted (less than 0.005mg per kcal per day vs. more) nor unadjusted (less than 8mg per day vs. more) previous dietary E intake was associated with any impairment
However, women who did not use vitamin E supplements at WHI baseline were at increased risk of mixed-domain impairment [odds ratio (OR), 1.88; 95% CI: 1.09 to 3.23)
In cross-sectional analyses, concurrent serum α-tocopherol was associated with both memory and mixed impairments, such that women in the lowest quintile of serum α-tocopherol were nearly twice as likely to also show signs of memory (1.92; 1.24 to 2.97) and mixed-domain (2.01; 1.13 to 3.57) impairments
Current vitamin E supplement use was not associated with risk of either impairment.

Multivariate Analyses

As in the bivariate analysis, neither low previous dietary vitamin E nor current vitamin E supplements use was significantly associated with either type of impairment
The magnitude of the association of previous supplement use with mixed-domain impairment was slightly smaller than that seen in the bivariate analysis (OR, 1.69 for nonusers) and no longer significant (95% CI: 0.9 to 3.12)
Adjusting for age and ANART score, being in the lowest quartile of serum α-tocopherol was associated with a twofold increased odds of memory impairment (OR, 2.02; 95% CI: 1.27 to 3.2) and mixed impairment (OR, 2; 05% CI: 1.04 to 3.85).

Author Conclusion:

This study examined the association between previous and current vitamin E supplement use and current serum α-tocopherol level and the presence of domain-specific cognitive impairment in a baseline series of neuropsychological tests in women aged 60 years and older. Previous vitamin E supplement use initially seemed to be associated with mixed-domain impairment but the association seemed to be confounded by age and ANART score.
Low serum α-tocopherol status was cross-sectionally associated with increased odds of memory and mixed cognitive impairments, whereas no association was seen between current vitamin E supplement intake and any type of cognitive impairment even though vitamin E supplement intake was reasonably well correlated with serum α-tocopherol status.
No association was observed between previous dietary vitamin E and cognitive impairment in either bivariate or adjusted analyses. This may have been due to low dietary intake compared to supplemental intake. Multivitamin supplements commonly have lower vitamin E content than single supplements. This was also reflected in the low correlation of previous dietary vitamin E intake with subsequent serum α-tocopherol level compared with that for previous supplemental intake noted above and is also reflected in the similar values of previous dietary vitamin E intake across quartiles of serum α-tocopherol.
The cross-sectional association of low serum α-tocopherol status with poorer cognitive function is consistent with many, though not all, previous studies. One possible explanation for the lack of cross-sectional association of vitamin E supplement use with cognitive impairment even though current supplement use was well correlated with serum status, could be that low serum α-tocopherol status may be a function of increased demand on available stores as well as lower intake. Also, because α-tocopherol is a fat-soluble micronutrient, serum levels might be indicative of longer-term as well as recent intake. If cognitive impairment is a result of accumulated damage to brain cells from oxidative and other injuries, it is to be expected that longer-term exposure to antioxidants or exposure earlier in the pathophysiologic process would yield a greater benefit than recent or concurrent exposure. The findings that previous vitamin E supplement use showed more evidence of association with cognitive impairments than current use coincide with such a hypothesis. Finally, it is possible that serum status could be associated with some other factor that could affect cognitive function.
Overall, the strength of the association seen between low serum α-tocopherol and risk of memory and mixed cognitive impairment is compelling and merits further exploration including future longitudinal analyses from the current study and exploration of additional variables that may influence serum tocopherol status.

Funding Source:

Government:

National Institute on Aging, National Heart, Lung and Blood Institute, US Department of Health and Human Services

Reviewer Comments:

The authors note the following limitations:

Since serum α-tocopherol was measured only as part of the CCW ancillary study, only cross-sectional associations could be examined for this variable
The use of multiple tests might increase the risk of an individual scoring low on one test by chance (false positive)
The women in the CCW ancillary study were not recruited from a community-based sample, the results may not be generalizable to all women aged 60 years and older in the Chicago metropolitan area
A larger sample or one with a larger percentage of impaired participants may have resulted in narrower CIs or allowed for control for more covariates.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	N/A
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	N/A

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		No
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	No
3.	Were study groups comparable?		N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	No
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	N/A
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	N/A
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes